The invention relates to DNA vaccines, or vaccines containing molecules encoded by such DNA, for the induction of specific, sustained high titer antibody responses. More specifically, the invention is directed to DNA vaccines that comprise recombinant expression constructs encoding a cell surface receptor antigen and one or more immune response altering molecules.
It is known in the immunological arts to provide certain vaccines according to a variety of formulations, usually for the purpose of inducing a desired immune response in a host. The immune system has been characterized as distinguishing foreign agents (or xe2x80x9cnon-selfxe2x80x9d) agents from familiar or xe2x80x9cselfxe2x80x9d components, such that foreign agents elicit immune responses while xe2x80x9cselfxe2x80x9d components are ignored or tolerated. Immune responses have traditionally been characterized as either humoral responses, in which antibodies specific for antigens are produced by differentiated B lymphocytes known as plasma cells, or cell mediated responses, in which various types of T lymphocytes act to eliminate antigens by a number of mechanisms. For example, CD4+ helper T cells that are capable of recognizing specific antigens may respond by releasing soluble mediators such as cytokines to recruit additional cells of the immune system to participate in an immune response. Also, CD8+ cytotoxic T cells that are also capable of specific antigen recognition may respond by binding to and destroying or damaging an antigen-bearing cell or particle.
Several strategies for eliciting specific immune responses through the administration of a vaccine to a host include immunization with heat-killed or with live, attenuated infectious pathogens such as viruses, bacteria or certain eukaryotic pathogens; immunization with a non-virulent infective agent capable of directing the expression of genetic material encoding the antigen(s) to which an immune response is desired; and immunization with subunit vaccines that contain isolated immunogens (such as proteins) from a particular pathogen in order to induce immunity against the pathogen. (See, e.g., Liu, 1998 Nature Medicine 4(5 suppl.):515.) Each of these approaches is compromised by certain trade-offs between safety and efficacy. Moreover, there may be certain types of desirable immunity for which none of these approaches has been particularly effective, including the development of vaccines that are effective in protecting a host immunologically against cancer, autoimmune disease, human immunodeficiency viruses or other clinical conditions.
In a number of contexts, it may be desirable to induce an immune response in a host that involves specific immune recognition of a cell surface receptor antigen (SRA). Such a target structure may be, for example, a host molecule, an altered (e.g., mutated, degraded, incompletely synthesized, conformationally changed, etc.) or inappropriately expressed host molecule or a foreign molecule. For example, numerous cell SRA have been implicated in cancer as unique or preferentially expressed markers of tumor cells, such that targeting an immune response to such SRA appears to be a useful strategy, albeit an approach still in need of refinement. (See, e.g., Pardoll, 1998 Nature Medicine 4(5 supp):525 and references cited therein.) In particular, many such approaches may provide induction of only weak or transient host immune responses, or of responses where induction of cell mediated and/or humoral immune response components is ineffective. Recent interest in therapeutic passive immunity conferred by the administration of SRA-specific monoclonal antibodies underscores the significance of SRA (see, e.g., Pietras et al., 1994 Oncogene 9:1829; Baselga et al, 1998 Canc. Res. 58:2825; Hoffmann et al., 1997 Anticanc. Res. 17:4419; Bier et al., 1998 Canc. Immunol. Immunother. 46:167; Petit et al., 1997 Am. J Pathol. 151:1523; Udayachander et al., 1997 Hum. Antibod. 8:60.) but does not offer the longer-lived protection afforded by a vaccine, which influences the host immune state.
Clearly there is a need for improved vaccines, and in particular for vaccines that are directed to inducing immune responses specific for cell surface receptor antigens. The present invention provides compositions and methods for cell surface receptor antigen specific vaccines, and other related advantages.
The invention provides compositions and methods for altering an immune response in a host in an antigen specific manner, wherein the antigen is a cell surface receptor antigen. Vaccines are provided that include a gene encoding a desired cell surface antigen receptor (or the expressed product) and one or more genes encoding immune response altering molecules (or the expressed products).
In one aspect, the invention is directed to a vaccine for eliciting or enhancing the titer of antibodies specific for a cell surface receptor antigen, comprising a recombinant expression construct comprising at least one promoter operably linked to a nucleic acid sequence encoding a cell surface receptor antigen, a nucleic acid sequence encoding a first immune response altering molecule and a nucleic acid sequence encoding a second immune response altering molecule, wherein the first and second immune response altering molecules are different from each other and are an accessory cell agent and a T cell agent. In one embodiment, the vaccine for eliciting or enhancing the titer of antibodies specific for a cell surface receptor antigen comprises the expression products of such a recombinant expression construct.
In another embodiment the invention provides a vaccine for eliciting or enhancing the titer of antibodies specific for a cell surface receptor antigen, comprising a first recombinant expression construct containing at least one promoter operably linked to a nucleic acid sequence encoding a cell surface receptor antigen and a nucleic acid sequence encoding a first immune response altering molecule; and a second recombinant expression construct containing a promoter operably linked to a nucleic acid sequence encoding a second immune response altering molecule, wherein the first and second immune response altering molecules are different from each other and are an accessory cell agent and a T cell agent. In a further embodiment, the vaccine for eliciting or enhancing the titer of antibodies specific for a cell surface receptor antigen comprises the expression products of such recombinant expression constructs.
In another embodiment the invention provides a vaccine for eliciting or enhancing the titer of antibodies specific for a cell surface receptor antigen, comprising a first recombinant expression construct containing at least one promoter operably linked to a nucleic acid sequence encoding a cell surface receptor antigen; a second recombinant expression construct containing a promoter operably linked to a nucleic acid sequence encoding a first immune response altering molecule; and a third recombinant expression construct containing a promoter operably linked to a nucleic acid sequence encoding a second immune response altering molecule, wherein the first and second immune response altering molecules are different from each other and are an accessory cell agent and a T cell agent. In a further embodiment, the vaccine for eliciting or enhancing the titer of antibodies specific for a cell surface receptor antigen comprises the expression products of such recombinant expression constructs.
In yet another embodiment, the invention provides a vaccine for eliciting or enhancing the titer of antibodies specific for a cell surface receptor antigen, comprising a first recombinant expression construct containing at least one promoter operably linked to a nucleic acid sequence encoding a cell surface receptor antigen; and a second recombinant expression construct containing at least one promoter operably linked to a nucleic acid sequence encoding a first immune response altering molecule and a nucleic acid sequence encoding a second immune response altering molecule, wherein the first and second immune response altering molecules are different from each other and are an accessory cell agent and a T cell agent. In a further embodiment, the vaccine for eliciting or enhancing the titer of antibodies specific for a cell surface receptor antigen comprises the expression products of such recombinant expression constructs.
These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth herein which describe in more detail certain aspects of this invention, and are therefore incorporated by reference in their entireties.